Tapentadol is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol. A particularly preferred form is the hydrochloride salt, 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride. Tapentadol is highly soluble drug and its solubility is pH dependent. It is considered as BCS class-I drug. Tapentadol hydrochloride may be depicted structurally as follows.

Tapentadol is a centrally acting analgesic having both μ-opioid receptor agonist and noradrenalin (norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition. This dual mode of action makes tapentadol particularly useful in the treatment of both nociceptive pain and neuropathic pain. Clinical trial evidence in acute and chronic non-cancer pain, cancer related pain and neuropathic pain supports an opioid-sparing effect that reduces some of the typical opioid-related adverse effects. Specifically, the reduction in treatment-emergent gastrointestinal adverse effects for tapentadol compared with equi-analgesic pure μ-opioid receptor agonist results in improved tolerability and adherence to therapy.
U.S. Pat. No. 6,248,737 discloses tapentadol and its hydrochloride salt. Tapentadol is available commercially as a brand name NUCYNTA® as 50 mg, 75 mg and 100 mg (free base equivalent) oral tablet, indicated for the relief of moderate to severe acute pain.
Oral administration of tapentadol results in low bioavailability (32%) because of extensive first-pass metabolism where about 97% of the administered tapentadol is metabolized. None of the metabolites contributes to the analgesic activity. Lipid solubility of tapentadol is approximately 2.8, which is comparatively low. Being an opioid analgesic, tapentadol is useful for the treatment of severe pain such as post-operative pain, cancer pain, etc. In such cases nausea and vomiting is a frequently associated problem, and thus, poor patient compliance is seen with oral administration. Moreover, for the treatment of breakthrough pain oral formulations are inadequate because absorption occurs at least 45 minutes after administration, which is not suitable in the treatment of breakthrough pain, as this delay in absorption is typically longer than the episode of breakthrough pain. The maximum serum concentration of tapentadol is typically observed at around 1.25 hours after oral dosing. The bitter taste of tapentadol is not patient friendly, and contributes to poor patient compliance.
Generally, opioids are known to show higher inter-subject variability (Clinical Pharmacology and Therapeutics; 2007; 81; 429-444). It has been observed that the route of administration may have an impact on inter-subject variability. It has been observed that variation of absorption after intranasal route may be a greater than intramuscular or subcutaneous route (Acta Anaesthesiol Scand 2002; 46; 759-770). Like other opioids, tapentadol also has high inter-subject variability, when given orally, as given in Tapentadol clinical study report synopsis R331333-PAI-30003 (KF 5503/32). High clearance of the tapentadol may be one of the reasons of this high inter-subject variability.
Thus, there exists need for an alternative dosage form of tapentadol which overcomes the above problems such as bitter taste, adverse effects, etc., and moreover provides quick onset of action with reduction of inter-subject variability and improved patient compliance.
International Publication No. WO 2005/020906 discloses intranasal opioid composition for pain management with improved bioavailability and improved patient compliance.
U.S. Patent Application Publication No. 2006/0110333 discloses a composition for nasal absorption of opioid comprises calcium carbonate and/or calcium phosphate having particle size of up to 500 μm, with lower risk of developing side effects as compared to oral route.
U.S. Pat. No. 5,629,011 discloses a composition for nasal administration comprises polar metabolite of opioid analgesic consists of glucoronides and ethereal sulphates of opioid analgesics.
U.S. Patent Application Publication No. 2010/0227921 discloses that tapentadol is associated with high inter-patient variability and therefore a uniform patient response may be lacking. Therefore, to overcome the problems, amino acids and peptide carbamate pro-drugs of tapentadol are prepared.
U.S. Patent Application Publication No. 2014/0170209 discloses a nasal composition comprising tapentadol or its pharmaceutically acceptable salts and at least one nasal carrier.
It is well known to the skilled person that apart from many factors, lipid solubility play crucial role in the absorption of drug through nasal mucosa. Drugs with high lipophilicity have higher tendency to get absorbed through nasal mucosa compared to almost negligible absorption of low lipophilicity drugs. It has been tested that, intranasal formulations of low lipophilicity drugs like morphine gives less bioavailability as compared to intravenous administration, when given in solution form. Therefore they are required to be given with agent like chitosan which provides longer time for drug transport across the nasal membrane, before the formulation is cleared by the mucociliary clearance mechanism.
The information disclosed herein is based on the observation that comparable tapentadol pharmacokinetic parameters may be achieved by intranasal administration of a lower tapentadol unit dose in a human when compared to oral administration of a higher tapentadol unit dose of an immediate release dosage form.